Blastocyst versus cleavage stage embryo transfer in assisted conception

Review question

We aimed to determine whether blastocyst stage (day 5 to 6) embryo transfer improves live birth rates following fresh transfer and cumulative pregnancy rates (following fresh and frozen-thawed cycles) compared with cleavage stage (day 2 to 3) transfer.

Background

Embryos from assisted reproductive technologies (ARTs, e.g. in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), thawed embryo cycles) are commonly transferred into a woman’s uterus at either the cleavage stage (day 2 to 3 after egg collection) or blastocyst stage (day 5 to 6 after egg collection). Until recently, most ART cycles transferred embryos at cleavage stage, however there has been a trend to transferring embryos at the blastocyst stage as this timing is about the same as natural cycle embryos moving into the uterus.

Study characteristics

We included 27 randomised controlled trials (RCTs), which included 4031 women. The evidence is current to April 2016.

Key results

There was low quality evidence for live birth and moderate for clinical pregnancy that fresh blastocyst stage transfer is associated with higher rates than fresh cleavage stage transfer. This suggests that if 29% of women achieve live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates (i.e. pregnancies from both fresh and thawed cycles deriving from a single egg collection procedure), but the evidence for this outcome was very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on cumulative rates of live birth and pregnancy. There was no evidence of a difference between the groups in multiple pregnancy and miscarriage rates, but the quality of evIdence was low. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage to enable ART consumers and service providers to make well informed decisions on the best treatment option available.

Quality of the evidence

The evidence was of low quality for most outcomes. The main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation, and unclear or high risk of attrition bias.

Authors' conclusions: 

There is low quality evidence for live birth and moderate quality evidence for clinical pregnancy that fresh blastocyst stage transfer is associated with higher rates than fresh cleavage stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates derived from fresh and frozen-thawed cycles following a single oocyte retrieval, but the evidence for this outcome was very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage to enable couples or women undergoing assisted reproductive technology (ART) and service providers to make well informed decisions on the best treatment option available.

Read the full abstract...
Background: 

Advances in cell culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage stage embryo transfer to blastocyst stage transfer. The rationale for blastocyst transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates.

Objectives: 

To determine whether blastocyst stage (day 5 to 6) embryo transfers improve the live birth rate, and other associated outcomes, compared with cleavage stage (day 2 to 3) embryo transfers.

Search strategy: 

We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2016, Issue 4), MEDLINE, EMBASE, PsycINFO, CINAHL, and Bio extracts from inception to 4th April 2016. We also searched registers of ongoing trials and the reference lists of studies retrieved.

Selection criteria: 

We included randomised controlled trials (RCTs) which compared the effectiveness of blastocyst versus cleavage stage transfers.

Data collection and analysis: 

We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth and cumulative clinical pregnancy rates. Secondary outcomes were clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos, and embryo freezing. We assessed the overall quality of the evidence for the main comparisons using GRADE methods.

Main results: 

We included 27 RCTs (4031 couples or women).

The live birth rate following fresh transfer was higher in the blastocyst transfer group (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.20 to 1.82; 13 RCTs, 1630 women, I2 = 45%, low quality evidence) following fresh transfer. This suggests that if 29% of women achieve live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer.

There was no evidence of a difference between the groups in rates per couple of cumulative pregnancy following fresh and frozen-thawed transfer after one oocyte retrieval (OR 0.89, 95% CI 0.64 to 1.22; 5 RCTs, 632 women, I2 = 71%, very low quality evidence).

The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer (OR 1.30, 95% CI 1.14 to 1.47; 27 RCTs, 4031 women, I2 = 56%, moderate quality evidence). This suggests that if 36% of women achieve clinical pregnancy after fresh cleavage stage transfer, between 39% and 46% would do so after fresh blastocyst stage transfer.

There was no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; 19 RCTs, 3019 women, I2 = 30%, low quality evidence), or miscarriage (OR 1.15, 95% CI 0.88 to 1.50; 18 RCTs, 2917 women, I2 = 0%, low quality evidence). These data are incomplete as under 70% of studies reported these outcomes.

Embryo freezing rates were lower in the blastocyst transfer group (OR 0.48, 95% CI 0.40 to 0.57; 14 RCTs, 2292 women, I2 = 84%, low quality evidence). This suggests that if 60% of women have embryos frozen after cleavage stage transfer, between 37% and 46% would do so after blastocyst stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; 17 RCTs, 2577 women, I2 = 36%, moderate quality evidence). This suggests that if 1% of women have no embryos transferred in (planned) fresh cleavage stage transfer, between 2% and 4% will have no embryos transferred in (planned) fresh blastocyst stage transfer.

The evidence was of low quality for most outcomes. The main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation, and unclear or high risk of attrition bias.

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